17-ethers of 2alpha-methyl-androstane-17beta-ol-3-one



United States Patent 0 3,294,786 17-ETHERS 0F 2 a-METHYL-ANDROSTANE- 17,8-0L-3-0NE 'Alexander D. Cross and Ian-T. Harrison, Mexico City,

Mexico, assignors to Syntex Corporation, Panama, Panama, a corporation of Panama No Drawing. Filed Feb. 24, 1965, Ser. No. 435,075

11 Claims. (Cl. 260-23955) The present invention relates to novel cyclopentano- ,phenanthrene derivatives and to a process for the pro- 3,294,786 Patented Dec. 27,1966

-In the above formula R represents hydrogenor-methyl Ice and R represents:

o on,

The novel compounds of the present invention represented by the above formula are anabolic-androgenic agents with a favorable anabolic-androgenic ratio. In addition they have anti-estrogenic, anti-gonadothrophic,

- anti-fibrall'atory and appetite stimulating properties. Fur- "premenstrual tension and suppress the output of 'the thennore, they lower the blood cholesterol level, relieve pituitary gland.

The novel compounds of the present invention are prepared by the process exemplified as follows:

In the above formulae R has the same meaning as set forth hereinbefore; and X represents chlorine or bromine.

In carrying out the process of the present invention the starting compound I which may be either Zen-methylandrostan-l7B-ol-3-one, or Zea-methyl-19-nor-andr0stan- 17,8-ol-3-one is treated with 2- methyl-l9-nor-androstanpyrane, preferably in toluene or benzene in the presence of p-toluenesulfonic acid, at room temperature for about 2 hours, to give the corresponding 17fi(2'-methyl-6'-acety1-tetrahydropyran-2'-yl)-oxy derivative (11).

Upon treatment of the starting compound (I) with 6- acetoxymethyl-S,6-dihydropyrane in a suitable solvent such as benzene or toluene, in the presence of p-toluenesulfonic acid at about room temperature for a period of time of the order of 2 hours, there is obtained the corresponding 17a 6'-acetoxymethyl-tetrahydropyran-2'-yl oxy derivative, which, upon conventional saponification in a basic medium affords the corresponding 17ot(6'-hydroxymethyl-tetrahydropyran-2-y1)-oXy derivative (III).

When the starting compound (I) is treated with a 2,3 dihalo-tetrahydropyran, for example 2,3-dibromo, or 2,3- dichloro tetrahydropyran, in a suitable solvent such as benzene or toluene, in the presence of a tertiary amine such as pyridine or triethylamine, for a period of time of the order of 24 hours at about room temperature, there is obtained the corresponding 17u(3-halo-tetrahydropyran-2'-yl)-oxy derivative (IV).

The starting compound (I) is treated with 6-fonmyl- 5,6-dihydro-py-ran, in a suitable solvent such as benzene or toluene, in the presence of p-toluenesulfonic acid for a period of time that may range between 30 minutes and 12 hours, at a temperature comprised between the reflux temperature of the reacting mixture and room temperature to give the corresponding 17a(3,7-epoXy-perhydrooxepin-2'-yl)-oxy derivative (V).

The following specific examples serve to illustrate but are not intended to limit the scope of the present invention:

Example I A mixture of 1 g. of Zu-methyI-androstan-17,8-ol-3-one, 1 g. of 2-methy1-6-acetyl-5,6-dihydropyran, 100 mg. of p-toluenesulfonic acid and 100 cc. of benzene was kept at room temperature for 2 hours, then it was successively washed with a dilute solution of sodium bicralbonate and water, dried over anhydrous soduim sulfate and evaporated to dryness. Crystallization of the residue from acetone-hexane yielded 17a(2'-methyl-6-acety1-tetradropyran-2-yl) oxy-2wmethylandrostan-3-one.

Za-methyl-19-nor-androstan-17B-ol-3-one, was treated by the same procedure, thus yielding 17u-(2'-methyl-6- acetyl-tetrahydropyran-2'-yl)-oxy 2a methyl-19-norandrostan-3-one.

Example II A mixture of 1 g. of 2m-methyl-androstan-17p-o1-3-one, 1 g. of 6-acetoxy-methyl-5,fi-dihydropyran, mg. of ptoluenesulfonic acid and 100 cc. of benzene was kept at room temperature for 2 hours. Then it was successively washed with a dilute aqueous sodium bircarbonate solution and water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was dissolved in methanol and there was added 1 g. of sodium hydroxide in 20 cc. of ethanol and the resulting mixture was refluxed for 1 hour. Water was added and the product was extracted with methylene chloride. The extract was evaporated to dryness and the residue crystallized from acetone hexane to give 17a (6'-hydroxymethyl-tetrahydropyran- 2'-yl)-oxy-2a-methyl-and.rostan-3-one.

2amethyl-19-nor-androstan-17fi-ol-3-one was treated according to the procedure just described, thus yielding 17a-(6'-hydroxymethyl-tetrahydropyran-2'-yl) oxy 2amethyl-19-nor-androstan-3-one.

Example 111 A mixture of 1 g. of 2a-methyl-androstan-17 3-ol-3-one,

2 g. of 2,3-dibromo-tetrahydropyran, 1 cc. of pyridine and cc. of benzene, was kept at room temperature for 24 hours. The resulting solution was washed successively with a 1% aqueous hydrochlori acid solution and Water, dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization of the residue from acetone-hexane afforded 17a-(3'-bromo-tetrahydropyran-2-yl)-oxy- 2a-met-hyl androstan-3-one.

Za-methyl-19-nor-androstan-l7p-ol-3-one was treated following exactly the above procedure, thus yielding c- (3-bromo tetrahydropyran 2 yl) oxy-2a-methyl-19- nor-androstan-3one.

2u-methyl-androstan-17fl-ol-3-one and 2a-methyl-19- nor-androstan-l7 8-ol-3-one were treated according to the above procedure, except that there was used 2,3-dichlor0 tetrahydropyran instead of 2-3-dibromo tetrahydropyran, thus affording respectively 17m-(3-chlorotetrahydropyran-2-yl)-oxy-2a-methyl-androstan-3 -one and 17a-(3'- chlorotetrahydropyran 2 yl)-oxy2a-methyl-19-nor-androstan-3-one.

Example IV A mixture of 1 g. of 2a-methyl-androstan-17 3-ol-3-one, 1 g. of 6-formyl-5,6-dihydropyran, 100mg. of p-toluenesulfonic acid and 100 cc. of benzene was refluxed for 30 minutes. Then it was cooled, washed successively with a dilute aqueous sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue crystallized from acetone-hexane to give 17a-(3',7'-epoxy perhydro oxepin-2'-yl)oxy-2amethyl-androstan-3-one.

2a-methyl-19-nor-androstan-17fl-ol-3-one was treated by the same procedure to five 17a-(3',7-ep0xy-perhydrooxepin-2-yl) -oxy-2a-methyl-19-nor-androstan-3-one.

We claim:

1. A compound of the following formula:

wherein R is selected from the group consisting of hydrogen and methyl and R is a member of the group consisting of 0 OH OH O I 1 O 0 o OH; OH;

and

9. 17a (3'-chloro-tetrahydropyran 2' yl) oxy-2amethyl-19-nor-androstan-3-one.

10. 17a-(3',7' epoxy perhydro-oxepin-2'-yl)-0xy-2amethyl-androstan-3-one.

11. 170: (3,7' epoxy-perhydro-0Xepin-2'-y1)-0xy-2amethyl-19-nor-androstan-3-one.

6 References Cited by the Examiner UNITED STATES PATENTS Y 3,158,607 11/1964 Cross 260--239.55

5 LEWIS GOTTS, Primary Examiner.

HENRY A. FRENCH, Assistant Examiner, 

1. A COMPOUND OF THE FOLLOWING FORMULA: 